The subject of drug delivery in general was reviewed by McCulloch and Shalaby [Tailored Polymeric Materials for Controlled Delivery Systems, ACS Symposium Series, Vol. 709 (1998)]. Part of this review pertained to the specific subject of intravaginal delivery which was discussed in a separate chapter (Chapter 2), and excerpts therefrom are included in the background information on the clinical effectiveness and attributes of intravaginal drug delivery noted below.
In recent years, a variety of women's health issues have generated considerable interest. Areas of particular importance have included obstetrics, medical terminations, contraception, infertility, sexually transmitted infections, and cancers of the reproductive tract. In the postmenopausal female, the reduction of endogenous estrogen has been shown to profoundly influence the skeletal and lower urogenital systems. Concurrently, a number of therapeutic strategies have been developed to improve treatment in these respective areas. While oral, intravenous, and transdermal routes of drug administration have been widely utilized, intravaginal drug delivery has been studied to a far lesser extent. Interestingly, there are many instances where intravaginal drug delivery may by ideal. For example, it is postulated that drug specificity for the reproductive tract may be more effectively achieved through intravaginal administration. Thus, elevated levels may be attained at a fraction of the oral or parenteral doses. A secondary benefit would be to improve patient compliance in terms of dosing frequency and/or systemic side effects. The rich vascular supply of the vagina also represents a rapid portal of entry when systemic drug levels are desired. Because of the anatomy, first-pass hepatic metabolism is bypassed which could be utilized to improve the relative bioavailability of certain agents.
Intravaginal drug delivery can be utilized for topical, local, or systemic effects. Topical administration has been used in the treatment of bacterial or fungal infections, atrophic vaginitis, and vaginal intraepithelial neoplasia. In terms of local therapy, vaginal drug administration has been used to treat stress urinary incontinence, labor induction, medical abortions, and infertility. The advantage of this route is the large surface area for drug absorption and ease of administration.
Current trends in intravaginal drug delivery are outlined below and include (1) labor induction; (2) hormone replacement therapy; (3) contraception; (4) infertility; (5) infectious diseases; and (6) gynecologic oncology.
Labor Induction—Spontaneous labor and delivery involve a sequence of events that include softening, or ripening, and effacement of the cervix. Labor induction is indicated when there is evidence of preeclampsia, diabetes, heart disease, or fetal-placental insufficiency. Prolonged labor in the context of an unfavorable cervix can increase the likelihood of numerous maternal and fetal complications such as infection, fetal distress/demise, the need for operative delivery, and postpartum hemorrhage. Pharmacological intervention is often implemented in an effort to “ripen” the cervix to facilitate vaginal delivery. Numerous studies dating back to the 1970's have documented the successful use of prostaglandins for labor induction through intracervical or intravaginal routes of administration. In recent years, dinoprostone (a synthetic prostaglandin E2) has been used for cervical ripening via vaginal administration. Early efforts utilized glycerol ester based formulations to deliver dinoprostone. Currently methylcellulose based materials and polyethylene oxide based hydrogels have been formulated for cervical ripening. Early concerns for these devices were related to dose dumping and ease of removal. While a burst release of drug in the early phase is difficult to avoid, signs and symptoms of toxicity have been less significant with current devices. The success of this system has largely been due to incorporating drug into hydrogel delivery systems where release is swelling-controlled and more predictable. In terms of retrieval, Cervidil® (a polyethylene oxide/urethane based hydrogel) is incorporated within a polyester net that can be used to remove the device should signs or symptoms of hyperstimulation result. It is thus expected that future delivery systems for labor induction will utilize both newer agents and/or polymeric systems. Although considerable interest has been placed on labor induction, it bears mention that other areas in obstetrics may benefit from intravaginal therapeutics. This includes the management of preterm labor with intravaginal tocolytic agents or through administration of antibiotics in the context of preterm rupture of membranes to prolong intrauterine gestational time. Labor augmentation in the latent period of stage I may be another phase of labor that could benefit from intravaginal therapeutics.
Hormone Replacement Therapy—Postmenopausal hormone replacement therapy (HRT) has received considerable attention in recent years. The dramatic shift away from their use in primary and secondary prevention for osteoporosis and increased risk in cardiovascular and hematologic events risk has been attributed to combination estrogen and progesterone therapy. However, estrogen-only therapy is still used for the treatment of vaginal and urogenital atrophy, and symptomatic relief of hot-flushes. Hormone replacement therapy can be achieved by many routes of administration. The most common of which are oral and transdermal administration. Vaginal estrogen creams have been in existence for many years. While systemic levels are achieved, daily administrations combined with patient compliance issues make this a less desirable approach to estrogen replacement. In response, vaginal estrogen-releasing rings have been developed to provide sustained drug release in a manner similar to transdermal delivery. Early investigators dispersed estradiol homogeneously into polysiloxane vaginal rings for this purpose. These delivery systems were capable of maintaining estradiol levels ranging from 109 pg/ml to 159 pg/ml for 3 months in postmenopausal volunteers. Serum levels could also be adjusted based on the loading dose of estradiol and surface area of the device. Estring® and other similar devices were later designed with an inner core or reservoir of estradiol and an outer polysiloxane sheath for diffusion-controlled release; and stable serum levels have been achieved for up to 3 months for the treatment of vaginal and urogenital atrophy.
Contraception—The development of new hormonal contraceptive modalities has been an ongoing effort for over forty years. Oral, injectable, and implantable contraceptives have all been widely used with exceptional efficacy. Intravaginal hormonal contraception was initially investigated using medroxyprogesterone. Medroxyprogesterone was homogeneously dispersed in cylindrical rings prepared from polysiloxane. Over a 28-day cycle, an absence of the midcycle luteinizing hormone (LH) surge was observed. Endometrial biopsies taken were found to be consistent with progestational effects. Furthermore, removal of the device resulted in prompt withdrawal bleeding. Similar designs have also been developed for 90-day clinical trials. Testing of a core designed vaginal ring containing norethindrone acetate and ethinyl estradiol revealed that ovulation and breakthrough bleeding were better controlled with average daily ethinyl estradiol release rates ranging from 30 to 65 mcg. However, unacceptably high levels of nausea resulted with the 65 mcg-daily release rates. Similar rings containing levonorgestrel have also been studied. Unlike the preceding ethinyl estradiol vaginal rings, there was greater individual variation in levonorgestrel levels, incomplete suppression of ovulation, and breakthrough bleeding.
Currently, intravaginal barrier and intrauterine contraceptive devices, with or without hormones, are available to inhibit ovulation and to prevent sperm migration into the cervix and fertilization. A literature search for non-hormonal, non-toxic and non-invasive contraceptive agents as well as the antimicrobial and antiviral agents revealed that metal ions and their derivatives, such as calcium chloride, sodium chloride, magnesium chloride, copper, and ferrous sulfate act as spermicidal and/or spermiostatic agents. Copper sulfate has been used in IUDs as a spermicidal agent. It is known that sulfhydryl groups are essential components of certain vital enzymes for stability of the sperm. The copper-based agents are toxic due to their sulfhydryl binding properties, and thus cause a direct deleterious effect on sperms. Copper also influences midcycle human cervical mucus by causing lysis of the mucus material, changing the physicochemical properties of the mucus resulting in a decrease in sperm penetration.
The medical management of abortions and ectopic pregnancies are two areas of converging study. Recent randomized trials utilized oral or intramuscular methotrexate with intravaginal administration of misoprostol to provide safe and efficacious medical abortions. These studies suggest that oral administration of methotrexate may have improved efficacy while minimizing systemic side effects. It is conceivable that intravaginal methotrexate administration may provide additional advantages in terms of higher local drug levels at lower doses. This could conceivably improve efficacy while further minimizing systemic side effects. Similarly, the medical management of ectopic pregnancies requires the intramuscular administration of methotrexate over 1 to 4 doses followed by leucovorin rescue. In this regard, the administration of an intravaginal methotrexate delivery system may be capable of releasing lower doses of drug over a predictable time course to improve efficacy and compliance while decreasing systemic side effects.
Infertility—Progesterone supplementation or replacement is widely implemented for assisted reproductive technology in the treatment of infertility. Oral administration of progesterone leads to extensive intestinal and hepatic metabolism. The standard of treatment for progesterone deficiency is through intramuscular administration which can be painful. Recently, an intravaginal progesterone gel (Crinone®) has been developed. The delivery system is a bioadhesive gel formulation prepared from polycarbophil. The gel is administered once or twice daily delivering 90 mg of micronized progesterone with each dose. Treatment may be continued for up to 12 weeks until placental autonomy is achieved. The manufacturers (Wyeth-Ayerst Laboratories) purport less drowsiness as compared to the oral form. This delivery system is also being studied in conjunction with oral estrogen for hormone replacement therapy.
Infectious Diseases—Interest in the administration of intravaginal agents for the treatment and prophylaxis of sexually-transmitted diseases and other infections has been considerable. Early efforts in this field had focused on treatment modalities for bacterial vaginosis. Bacterial vaginosis is a syndrome in women of reproductive age where the normal Lactobacillus-dominated vaginal microflora is replaced by high concentrations of mixed anaerobic and facultative flora. Typically, this includes Peptostreptococcus sp., Gardnerella vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum. It is considered to be the most common vaginal infection and has been associated with an increased risk of preterm labor and delivery, premature rupture of membranes, chorioamnionitis, and pelvic inflammatory disease. Topical administration of clindamycin or metronidazole has been most successful in the treatment of bacterial vaginosis. Studies on the efficacy of 0.1% to 2.0% clindamycin creams administered daily for seven days in non-pregnant women indicated that the 2% cream had the greatest effect on bacterial vaginosis-associated flora with a 94% resolution of bacterial vaginosis both one week and one month after treatment. Similar findings have been reported elsewhere. The efficacy of intravaginal clindamycin has also been shown to be similar to oral metronidazole. The bioavailability of clindamycin has been shown to be minimal ranging from 2.7% to 4.7%. Intravaginal metronidazole has been studied to improve patient compliance and decrease side systemic side effects as seen with the oral regimen. Administration of intravaginal sponges containing either 250 mg (twice-daily for two days) or one gram (once-daily for three days) of metronidazole to a small group of women led to a cure rate of 85% after one week. Failure rates after one month were 42% in the low dose and 12% in the high dose group. Systemic side effects such as nausea, headache and metallic taste were slightly more frequent in patients using the higher dose sponge. In another study, the efficacy of 5 gm metronidazole gels (0.75%) administered twice-daily for 5 days. A clinical cure rate of 87% was observed after 9 to 21 days with a recurrence rate of 15% after one month. Furthermore, there were no significant side effects noted in the treatment group.
Current standards in the treatment of sexually transmitted diseases have focused on oral and intravenous administration of antibiotics and antiviral agents. While little has been done in terms of intravaginal treatment strategies, a growing interest in prophylaxis has emerged using vaginal microbiocides and antiviral agents. The ultimate goal is to develop a vaginal delivery system that has activity against a broad spectrum of pathogens, including human immunodeficiency virus (HIV). A number of compounds have been considered such as benzalkonium chloride, chlorhexidine, nonoxynol-9, and polymixin B. In terms of HIV transmission, both virucidal agents and biomaterials that prevent HIV adsorption/fusion are being studied. Although this area is still in its infancy, the growing urgency for prevention strategies will quickly attract many investigators from multidisciplinary backgrounds to study this problem. It is clear, however, that the active agent as well as the delivery system will play an equal role in optimizing efficacy.
Vaginitis Due to Vaginal Infection:
Bacterial Vaginosis (BV) is the most common cause of vaginitis symptoms among women of childbearing age. Previously called non-specific vaginitis or Gardnerella-associated vaginitis. BV is associated with sexual activity and can be sexually transmitted. It can be treated with antibiotics such as metronidazole or clindamycin.
Vaginal Yeast Infection or valvovaginal candidiasis is a common cause of vaginal irritation. Several factors are associated with increased symptomatic yeast infection in women, including pregnancy, uncontrolled diabetes mellitus, and use of oral contraceptives or antibiotics. Other factors that may increase the incidence of yeast infection include using douches, perfumed feminine hygiene sprays, and topical antimicrobial agents, and wearing tight, poorly ventilated clothing and underwear. Whether or not yeast can be transmitted sexually is unknown. Various antifungal vaginal medications are available. These include antifungal creams, tablets, or suppositories (butoconazole, miconazole, clotrimazole and tioconazole), over-the-counter for use in the vagina.
Trichomaniasis is commonly referred to as “trich” and is a common STD. It is caused by a single-celled protozoan parasite, Trichomonas Vaginalis. Metronidazole is the drug used for treatment.
Gynecologic Oncology:
Intravaginal administration of chemotherapy has been evaluated for the treatment of vaginal and cervical dysplasias. The rational is based on the assumption that higher localized levels can be achieved at a fraction of the intravenous dose with minimal systemic side effects. A case report in 1975 was the first to describe the topical administration of 5-fluorouracil (5-FU) for treatment of multifocal vaginal intraepithelial neoplasia. Twice daily administration of 5% 5-FU cream for two weeks resulted in benign cytological findings for up to a 15-month follow-up period. However, evidence of excoriation and thinning of the vaginal wall was noted one month after treatment. This resulted in some dyspareunia for up to 7 months. Similar efficacy and side effects were later noted using different 5-FU concentrations and dosing regimens. In another study, the administration of 20% 5-FU over monthly. 5-day courses in patients with post-irradiation vaginal carcinoma in-situ indicated that seven of the eight women studied had an initial complete response with three of the patients developing a recurrence after treatment was stopped. Re-treatment, however, resulted in a complete response in two of the three recurrences. Meanwhile, it was noted that most of the patients developed vulvovaginitis that was controlled by sitz baths and analgesics. Human Papillomavirus (HPV)-associated lesions of the vulva and vagina have been treated with topical 5-FU as well. Prophylactic topical 5-FU following ablative treatment was studied using biweekly doses of 5% 5-FU creams for six months. Recurrences developed in 13% of the cases as compared to 35% in the control group. It was also noted that maintenance therapy was most effective in women with multiple lesions, multiple organ involvement (vulva, vagina, cervix, anus, distal urethra), or a depressed immune system. Similar findings were noted using a once-a-week dosing regimen. In terms of side-effects, however, long-term topical administration of 5-FU can lead to chronic ulcerative changes in the vagina, particularly after 10 weeks of therapy. Associated symptoms also included sero-sanguinous or watery discharge, post-coital spotting or bleeding, irregular bleeding, and pain. Conservative treatment with estrogens and/or cauterizing agents did not facilitate healing. However, excision of the ulcer with primary closure was found to be curative.
The treatment of cervical intraepithelial neoplasia (CIN) and its effect on the regression CIN II with topically administered all-trans-retinoic acid (RA) has been studied. The device used to deliver RA was a collagen sponge inserted into a cervical cap comprised of a bioadhesive hydrogel. Patients returned at 3 and 6 months for follow-up as well as maintenance treatment consisting of daily RA for 2 days. The results showed that locally applied RA (daily for 4 days) led to complete histologic regression of CIN II in 43% of the patients. No treatment effect was observed in cases of severe dysplasia (CIN III). Side effects included cervical inflammation by colposcopic evaluation, mild vaginal inflammation, and vulva burning/irritation during initial treatment. Intravaginal administration of interferon gamma has also been studied for the treatment of CIN. In terms of cervical cancer, some investigators have proposed intravaginal administration of cisplatin. However, very few case reports exist. Thus, any perceived benefit is purely speculative at this time. The preceding discussion illustrates the possible benefit of intravaginal chemotherapy in the treatment of vaginal and even cervical dysplasias. Again, the choice of the chemotherapeutic agent, mode of delivery, and type of delivery system will be equally as important if efficacy is to be optimized.
It is well acknowledged that intravaginal drug delivery is largely in its infancy compared to other routes of drug administration. It is also well recognized that successful development of novel intravaginal drug delivery systems is intimately related to the successful development of novel polymeric carrier systems for optimized drug efficacy, patient compliance, and safety. And this invention deals with novel polymeric systems for intravaginal drug delivery with attributes that exceed those disclosed in the prior art. Examples of intravaginal delivery systems of the prior art which are most relevant to the present invention are summarized below:
(1) U.S. Pat. No. 6,416,780 describes an intravaginal shell or core drug delivery device suitable for administration of female humans or animals comprises testosterone or a testosterone precursor in a polymer matrix, surrounded by a sheath, and is capable of releasing the testosterone or testosterone precursor in a substantially zero-order pattern on a daily basis for at least three weeks. The device is intended to restore circulating testosterone levels to the normal physiological range or to induce supra-therapeutic testosterone levels.
(2) U.S. Pat. Nos. 6,127,327 and 6,086,909 deals with the transvaginal delivery into the uterus and refers to a special circulation which exists between the vagina and the uterus, which permits preferential uptake of the drug into the uterus when the drug is administered intravaginally or transvaginally using an appropriate device. Such device is, preferably, a medicated tampon, vaginal ring, medicated pessary, medicated cervical cup, medicated tablet, medicated suppository or any other device which is suitable for intravaginal insertion.
(3) U.S. Pat. No. 6,416,779 discloses a medicated intravaginal device for delivery of an antifungal, antiviral, antibacterial, trichomonicidal or parasiticidal pharmaceutical agent intravaginally to a female vagina or transvaginally to uterus or general circulation through a vaginal mucosa, said device comprising a vaginal tampon, vaginal ring, vaginal cup, vaginal tablet, vaginal sponge, or vaginal bioadhesive tablet incorporated with a composition comprising from about 0.1 to about 10%, by weight, of an active agent. The antifungal agent is selected from the group consisting of miconazole, terconazole, isoconazole, fenticonazole, fluconazole, nystatin, ketoconazole, clotrimazole, butoconazole, econazole, tioconazole, itraconazole, 5-fluoracil and metronidazole; the antiviral agent selected from the group consisting of acyclovir, femciclovir, valacyclovir and AZT; the antibacterial agent selected from the group consisting of clindamycin, tetracycline, amoxicillin, ampicillin, erythromycin, doxycycline, lumefloxacin, norfloxacin, afloxam, ciproflaxin, azitromycin and cefltoxine; the antichlamydial agent selected from the group consisting of tetracycline, doxycycline and erythromycin; the trichomonicidal or parasiticidal agent selected from the group consisting of metronidazole and clotrimazol.
(4) U.S. Pat. No. 6,299,894 describes a delivery device for the controlled release of the therapeutically active agent gestodene, over a prolonged period of time, at a release rate of 0.1-300 .mu.g/day, said device comprising a core comprising at least said therapeutically active agent, and a membrane encasing said core wherein said membrane is made of an elastomer. According to the invention, the elastomer is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, and the release rate of said therapeutically active agent of said delivery device is regulated by the amount of said 3,3,3-trifluoropropyl groups.
The device can be made according to well-known technology, which can be a T-shaped insert made of plastic materials such as polyethylene. The body consists of an elongate member (stem) having at one end a transverse member comprising two wings. The elongate member and the transverse member form a substantially T-shaped piece when the device is positioned in the uterus. The device has an attached thread long enough to protrude out of the cervical canal when the device is in position in the uterus. Intrauterine systems (IUSs) releasing drugs have a drug reservoir adjusted around the elongate member. This drug reservoir is preferably a matrix which consists of the elastomer matrix with the active agent(s) dispersed therein. Preferably, the matrix is encased in a membrane. The membrane is usually made of an elastomer.
(5) U.S. Pat. No. 6,103,256 deals with an intravaginal drug delivery device comprising at least one active agent dispersed in a polymer matrix, wherein the concentration of active agent at the outer surface of the device at the time of use is not substantially higher than the concentration of the active agent in the remainder of the device, a method of treatment therewith and a process for its preparation. According to this invention, a drug such as estrogen may be administered intravaginally using creams, solutions or tablets. However, as with oral administration, a bolus rather than sustained delivery of estrogen is produced which requires multiple doses. In order to achieve controlled, sustained release of estrogen over a period of months, an intravaginal device, conveniently in the shape of a ring, has proved to be most effective. A particular advantage associated with the use of vaginal rings is that these can be self-inserted and removed from the vagina.
(6) U.S. Pat. No. 4,795,761 describes a contraceptive sponge that may be prepared by absorbing the active constituents into a biocompatible, bioinsoluble, non-toxic sponge-like soft polymer. Suitable polymers for this use are well known in the art, for example 2-hydroxyethyl methacrylate. In another aspect of this invention, a controlled delivery device consists of the active constituents absorbed in a biocompatible, bioinsoluble, flexible, silicone rubber matrix, especially a dimethylpolysiloxane.
(7) U.S. Pat. No. 6,572,874 deals with devices, methods, and compositions for vaginal delivery of bisphosphonates. Intravaginal delivery of bisphosphonates is an alternative route for systemic treatment of osteoporosis and other related bone and skeleton diseases. The composition can be formulated as a suppository, cream, gel, foam, ointment, capsule, capsule containing microparticles, free-microparticles, or microcapsules.
(8) U.S. Pat. No. 5,069,906 describes numerous contraceptive devices that have been developed to eliminate the disadvantages of current, reusable diaphragms. Prior art annular devices provide controlled release of surfactant-type spermicides in the vagina, but that does not act as a barrier to sperm deposition on or in the area of the cervix. Devices with compartments that substantially cap or block the cervix and provide controlled release of spermicidal surfactants have been disclosed; however, these devices are not disposable, and they are designed to remain in the vagina and release spermicide during the time between menstrual periods. Because of this length of use, they may develop problems with infection, odor, or discomfort, and they are less suited for women who engage in sexual intercourse infrequently.
(9) U.S. Pat. No. 4,983,393 describes a solid, shaped, integral, solidified composition suitable for use as an intravaginal insert, capable of dissolution or disintegration in the presence of vaginal fluids, and comprising agarose in an amount from about 0.1 percent to about 4 percent by weight, agar in the amount of about 0.1 percent to about 4 percent by weight, saline solution, high molecular weight glycosaminoglycans of about 100,000 Daltons to about 1,000,000 Daltons in an amount from about 0.1 percent to about 20 percent by weight, collagen in an amount from abut 0.1 percent to about 20 percent by weight, fibrin in an amount from about 0.1 percent to about 20 percent by weight and an enzyme selected from the group consisting of agarase, protease, collagenase and saccharidase, said enzyme being present in said composition in an amount from about 0 percent to about 10 percent by weight.
Unfortunately, most of the polymeric carriers used in the prior art and all the ones described above for the production of intravaginal drug delivery systems were non-absorbable/non-biodegradable. This was pointed out in U.S. Pat. Nos. 5,176,907 and 6,503,528 as major drawbacks and attributes of systems based on absorbable/biodegradable polymers were emphasized as discussed below.
For a non-biodegradable matrix, the steps leading to release of the therapeutic agent are water diffusion into the matrix, dissolution of the therapeutic agent, and diffusion-controlled release of agent through polymer matrix. As a consequence, the mean residence time of the therapeutic agent existing in the soluble state is longer for a non-biodegradable matrix than for a biodegradable matrix where extended diffusion times through tortuous channels is not required. Since many pharmaceuticals may have brief activity after solubilization under physiologic conditions in the vagina, it is likely that the therapeutic agent is decomposed or inactivated inside the non-biodegradable matrix before it can be released. This issue is particularly significant for many bio-macromolecules and smaller polypeptides, since these molecules are generally unstable in buffer and have low permeability through polymers. In fact, in a non-biodegradable matrix, many bio-macromolecules will aggregate and precipitate, clogging the channels necessary for diffusion out of the carrier matrix. This problem is largely alleviated by using an absorbable/biodegradable matrix that allows for degradation-controlled release of the therapeutic agent. Absorbable/biodegradable polymers differ from non-absorbable/non-biodegra-dable polymers in that they are absorbed, biodegraded, or simply consumed during therapy. This usually involves breakdown of the polymer to its monomeric subunits, which should be biocompatible with the surrounding tissue. The life of an absorbable/biodegradable polymer in vivo depends on its chemical structure, molecular weight, and degree of crosslinking; the greater the molecular weight and degree of crosslinking, the longer the life. The most highly investigated absorbable/biodegradable polymers are polylactic acid (PLA), polyglycolic acid (PGA), copolymers of PLA and PGA, polyamides, and copolymers of polyamides and polyesters. PLA, sometimes referred to as polylactide, undergoes hydrolytic de-esterification to lactic acid, a normal product of muscle metabolism. PGA, or polyglycolide, is chemically related to PLA and is commonly used for absorbable surgical sutures. However, the use of PGA in controlled-release implants has been limited due to its low solubility in common solvents and subsequent difficulty in fabrication of devices. The copolymers of lactide and glycolide, commonly known as PLGs, are widely used in drug delivery systems for their solubility in common solvents and ease of processing into different forms of devices. An advantage of an absorbable/biodegradable material is the elimination of the need for surgical removal after it has fulfilled its mission. The appeal of such a material is more than simply for convenience. From a technical standpoint, a material that absorbs or biodegrades gradually and is excreted over time can offer many unique advantages.
An absorbable/biodegradable therapeutic agent delivery system has several additional advantages: (1) the therapeutic agent release rate is amenable to control through variation of the matrix composition; (2) implantation can be done at sites difficult or impossible for retrieval; and (3) delivery of unstable therapeutic agents is more practical. This last point is of particular importance in light of the advances in molecular biology and genetic engineering which have led to the commercial availability of many potent bio-macromolecules. The short in vivo half-lives and low gastrointestinal (GI) tract absorption of these polypeptides render them totally unsuitable for conventional oral or intravenous administration. Also, because these substances are often unstable in buffer, such polypeptides cannot be effectively delivered by pumping devices.
In its simplest form, an absorbable/biodegradable therapeutic agent delivery system consists of a dispersion of the drug solutes in a polymer matrix. The therapeutic agent is released as the polymeric matrix decomposes, or biodegrades into soluble products that are excreted from the body. Several classes of synthetic polymers, including polyesters, polyamides, polyurethanes, polyorthoesters, and polyanhydrides have been studied for this purpose.
Canadian Patent No. 2,420,348 is directed to a non-hormonal, biodegradable intravaginal device for the delivery of spermiostatic, spermicidal and anti-infectious agents. The device, subject of that patent, was described as a flexible structure, impregnated with an effective concentration of biocompatible spermiostatic agents and/or spermicidal agents and/or anti-infective agents. The basic design of the delivery vehicle was described as a hydrogel core-sheath configuration made of biocompatible and biodegradable polymers, which may be either natural and/or synthetic. The biodegradable hydrogel core or matrix component of the device comprises a polysaccharide selected from the group consisting of dextran-maleic acid, dextran-acrylate and dextran-allyl isocyanate, wherein said hydrogel matrix is coated with one or more biodegradable polyglycolide(s), polylactide(s), copolymers of polyglycolide and polylactide and mixture thereof. The spermiostatic, agent subject of CA 2,420,348, is selected from the group consisting of calcium chloride, ferrous sulfate, copper sulfate, ferrous gluconate and mixtures thereof. The patent also disclosed a method for maintaining the vaginal pH at about 5.6 using L-ascorbic acid as part of the matrix composition. In addition to its use as a pH controlling agent, L-ascorbic acid established property as a reducing agent was associated with its effect on increasing the viscosity of the cervical mucus, through conformational changes, and hence interfere with sperm mobility.
Meanwhile, it was noted in U.S. Pat. No. 5,176,907 that all prior art pertaining to absorbable/biodegradable polymers possess some degree of imperfection, such as weak mechanical strength, unfavorable degradation characteristics, toxicity, inflexibility, or fabrication difficulty. Interestingly, a number of similar design defects are implicit in the teaching of CA 2,420,348 where (1) an aqueous hydrogel matrix is coated with a hydrolyzable polyester coating, which represents a chemical incompatibility that cannot be tolerated in any product with an acceptable shelf-life; (2) a hydrophobic coating is applied onto an aqueous matrix, and hence creates an opportunity for cracking and peeling of said coating; and (3) a hydrogel matrix having no mechanical strength is not expected to provide the required resistance to dislocation and subsequent outward migration from the vagina. Although these absorbable/biodegradable polymers have a broad range of potential utility, there is no one single material available that could satisfy all requirements imposed by different applications. Accordingly, there is a definite need to develop new absorbable/biodegradable polymers in traditional or novel forms of drug delivery systems. This provided an incentive to pursue the novel delivery systems subject of this invention. And contrary to all the bioabsorbable/biodegradable polymers of the prior art, the present invention deals with a novel fiber-reinforced device for the intravaginal release of bioactive agents that is controlled not only by the drug/matrix interaction, but also by the properties of the reinforcing fiber component of the device. Such a novel device allows its applicability to a broad range of bioactive agents at a wide range of therapeutically effective dose.